1-(3-heteroarylpropyl- or -prop-2-enyl)-4-benzylpiperidines used as NMDA receptor antagonists

ABSTRACT

Piperidine derivatives of the formula I                    
     and their physiologically acceptable salts 
     in which X, Y, Z, R 1 , R 2 , R 3  and R 4  are as defined in claim 1 
     can be as excitatory amino acid antagonists for combating neurodegenerative disorders including cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer&#39;s disease, Parkinson&#39;s disease and Huntington&#39;s disease, cerebral ischaemias, infarcts and psychosis.

The invention relates to piperidine derivatives of the formula I

in which

X is 0, NR¹, S or (CH₂)_(n),

Y is CH,

Z is CH,

where Y and Z together can also be C═C,

R¹, R² and R3 each independently of one another are H or A,

R⁴ is H, Hal, A or OA,

A is alkyl having 1-6 carbon atoms,

Hal is F, Cl, Br or I and

n is 1, 2 or 3,

and their physiologically acceptable salts.

Benzylpiperidine derivatives having a high affinity for binding sites ofamino acid receptors are known, for example, from EP 0 709 384 A1.

The object of the invention was to discover novel compounds havinguseful properties, especially compounds which can be used for preparingmedicaments.

It has been found that the compounds of the formula I and their saltsare not only well tolerated but also have very useful pharmacologicalproperties. In particular, they have a very high affinity for bindingsites of amino acid receptors, especially for the ifenprodil bindingsite on the NMDA receptor (NMDA=N-methyl-D-aspartate), which modulatesthe polyamine binding site allosterically.

The binding test for [³H]-ifenprodil can be conducted by the method ofSchoemaker et al., Eur. J. Pharmacol. 176, 249-250 (1990). The compoundsare suitable for treating neurodegenerative disorders, includingcerebrovascular diseases. The novel compounds can also be used as ananalgesic or anxiolytic and in the treatment of epilepsy, schizophrenia,Alzheimer's disease, Parkinson's disease and Huntington's disease,cerebral ischaemias or infarcts. Furthermore, they are suitable fortreating psychoses caused by excessively high amino acid levels.

The [³H]-CGP-39653 binding test for the glutamate binding site of theNMDA receptor can be conducted, for example, by the method of M. A.Stills et al., described in Eur. J. Pharmacol. 192, 19-24 (1991). Thetest for the glycine binding site of the NMDA receptor can be conductedby the method of M. B. Baron et al., described in Eur. J. Pharmacol.206, 149-154 (1991).

The activity against Parkinson's disease, i.e. the potentiation of theL-DOPA-induced contralateral pivoting in hemiparkinsonian rats, can bedetected by the method of U. Ungerstedt and G. W. Arbuthnott, Brain Res.24, 485 (1970).

The compound is particularly suitable for treatment or prophylaxis ofstrokes and for protection against and treatment of cerebral oedemas andstates of undersupply of the central nervous system, especially hypoxiaor anoxia.

The activities referred to can, moreover, be detected or checked bymethods such as those described in the following literature references:

J. W. McDonald, F. S. Silverstein and M. V. Johnston, Eur. J. Pharmacol.140, 359 (1987); R. Gill, A. C. Foster and G. N. Woodruff, J. Neurosci.7, 3343 (1987); J. B. Bederson et al., Stroke, 17, 472-476 (1986); S.Brint et al., J. Cereb. Blood Flow Metab. 8, 474-485 (1988).

The literature references listed below disclose a variety of antagonistswhich are able to block different binding sites of the NMDA receptor:

W. Danysz, C. G. Parsons, I. Bresink and G. Quack, Drug, News &Perspective 8, 261 (1995), K. R. Gee, Exp. Opin. Invest. Drugs 3, 1021(1994) and J. J. Kulagowski and L. L. Iversen, J. Med. Chem. 37, 4053(1994).

Ifenprodil and eliprodil, of the formulae IIIa and IV respectively, areable to block the NMDA receptor by interacting with the modulatorypolyamine binding site (C. J. Carter, K. G. Lloyd, B. Zivkovic and B.Scatton, J. Pharmacol. Exp. Ther. 253, 475 (1990)).

Since ifenprodil and eliprodil interact with the polyamine binding siteon the NMDA receptor, the antagonistic activity of the compounds of theinvention can be determined using a spermine-stimulated [³H]-MK-801(dizocilpine) binding test.

In the presence of saturation concentrations of glycine and NMDA,spermine is still able to increase the binding of MK-801, which isinhibited by ifenprodil, eliprodil and, very effectively, by thecompounds of the invention.

In addition, the compounds of the invention can be tested in a [³H]-GABA(γ-aminobutyric) release test, in analogy to J. Dreijer, T. Honoré andA. Schousboe, J. Neurosci. 7, 2910 (1987), which is an in vitro modeldescribing the antagonistic function in the cell.

The invention provides, accordingly, the compounds of the formula Iaccording to claim 1 and/or their physiologically acceptable salts asantagonists to receptors of excitatory amino acids, such as glutamicacid or its salts.

The invention provides, in particular, the compounds of the formula Iaccording to claim 1 and/or their acceptable salts as excitatory aminoacid antagonists for combating neurodegenerative disorders includingcerebrovascular diseases, epilepsy, schizophrenia, Alzheimer's disease,Parkinson's disease and Huntington's disease, cerebral ischaemias,infarcts and psychoses.

The invention also provides for the use of the compounds of the formulaI according to claim 1 and/or their physiologically acceptable salts forpreparing a medicament for combating neurodegenerative disordersincluding cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer'sdisease, Parkinson's disease and Huntington's disease, cerebralischaemias, infarcts and psychoses.

The compounds of the formula I can be employed as an active principle ofmedicaments in human and veterinary medicine.

The invention additionally provides a process for preparing thecompounds of the formula I according to claim 1 and theirphysiologically acceptable salts, characterized in that

a) a compound of the formula II

 in which

L is Cl, Br, I, OH or a reactively esterified OH group,

and X, Y, Z, R¹, R² and R³ are as defined in claim 1

 is reacted with a compound of the formula III

in which R⁴ is as defined in claim 1, or

b) a compound of the formula I in which X, R¹, R², R³ and R⁴ are asdefined in claim 1, and Y and Z together are C═C is hydrogenated, or

c) water or L′H is eliminated from a compound of the formula I in whichX, R¹, R³ and R⁴ are as defined in claim 1,

Y is CH,

Z is CH and

R² is OH or L′, in which L′ is Cl, Br, I, or a reactively esterified OHgroup, and/or

d) a compound of the formula I is converted by treatment with an acidinto one of its salts.

Accordingly, the invention provides in particular those compounds of theformula I in which at least one of the stated radicals has one of thepreferred definitions indicated above. Some preferred groups ofcompounds can be expressed by the following subformulae Ia to Ic, whichcorrespond to the formula I and in which those radicals not identifiedin any more detail are as defined for the formula I, but in which

in Ia

R¹ is H;

in Ib

R¹ is H and

X is O, NR¹ or S;

in Ic

R¹ is H,

X O, NR¹ or S,

R² is H,

R³ is H or A and

R⁴ is Hal.

Alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms, and is preferablymethyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, and alsopreferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, but alson-pentyl, neopentyl, isopentyl or hexyl.

The compounds of the formula I and also the starting materials for theirpreparation are otherwise prepared by methods known per se, as aredescribed in the literature (e.g. in the standard works such asHouben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag,Stuttgart) under reaction conditions which are known and suitable forthe stated reactions. In this context it is also possible to make use ofvariants which are known per se but are not mentioned in any greaterdetail here.

If desired, the starting materials can also be formed in situ such thatthey are not isolated from the reaction mixture but instead areimmediately reacted further to give the compound of the formula I.

The compounds of the formula I can preferably be obtained by reactingcompounds of the formula II with compounds of the formula III.

The starting compounds of the formula II are generally novel. However,they can be prepared by methods which are known per se.

In the compounds of the formula II, L is preferably Cl, Br, I, OH or areactively modified OH group such as alkylsulfonyloxy having 1-6 carbonatoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).

The reaction of the compounds of the formula II with compounds of theformula III generally takes place in an inert solvent, in the presenceof an acid-binding agent, preferably an organic base such astriethylamine, dimethylaniline, pyridine or quinoline.

It may also be advantageous to add a hydroxide, carbonate or bicarbonateof an alkali metal or alkaline earth metal, or another salt of a weakacid of the alkali metals or alkaline earth metals, preferably ofpotassium, sodium, calcium or caesium.

Depending on the conditions employed, the reaction time lies betweenseveral minutes and 14 days, the reaction temperature between about −30°and 140°, normally between −10° and 90° and, in particular, betweenabout 0° and about 70°.

Examples of suitable inert solvents are hydrocarbons such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbonssuch as trichloroethylene, 1,2-dichloroethane, carbon tetra-chloride,chloroform or dichloromethane; alcohols such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers such as ethylene glycol monomethyl or monoethyl ether(methyl glycol or ethyl glycol), ethylene glycol dimethyl ether(diglyme); ketones such as acetone or butanone; amides such asacetamide, dimethylacetamide or dimethylformamide (DMF); nitriles suchas acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbondisulfide; carboxylic acids such as formic acid or acetic acid; nitrocompounds such as nitromethane or nitrobenzene; esters such as ethylacetate, water, or mixtures of the stated solvents.

Compounds of the formula I in which Y and Z are each CH can also beprepared, preferably, by hydrogenation from the compounds of the formulaI in which Y and Z together are C═C.

For this purpose it is preferred to employ catalytic hydrogenation with,for example, palladium on active carbon and hydrogen.

Examples of suitable catalysts for the catalytic hydrogenation are noblemetal catalysts and nickel and cobalt catalysts. The noble metalcatalysts can be on supports (e.g. platinum or palladium on carbon,palladium on calcium carbonate or strontium carbonate), can be oxidecatalysts (e.g. platinum oxide), or can be finely divided metalcatalysts. Nickel catalysts and cobalt catalysts are judiciouslyemployed as Raney metals, nickel also on kieselguhr or pumice assupport. The hydrogenation can be conducted at room temperature andatmospheric pressure or else at elevated temperature and/or increasedpressure. It is preferred to operate at pressures between 1 and 100 barand at temperatures between −80 and +150° C., primarily between roomtemperature and 100° C. The reaction is judiciously conducted in theacidic, neutral or basic range and in the presence of a solvent, such aswater, methanol, ethanol, isopropanol, n-butanol, ethyl acetate,dioxane, acetic acid or THF; mixtures of these solvents can also beemployed.

Compounds of the formula I in which Y and Z together are C═C canpreferably be obtained from compounds of the formula I in which

X, R¹, R³ and R⁴ are as defined in claim 1,

Y is CH,

Z is CH and

R² is OH or L′, in which L′ is Cl, Br, I, OH or a reactively esterifiedOH group,

by eliminating water or L′H from these compounds.

Elimination is preferably conducted with aqueous acids, especiallyaqueous mineral acids.

L′is, for example, preferably Cl, Br, I or a reactively modified OHgroup such as alkylsulfonyloxy having 1-6 carbon atoms (preferablymethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms(preferably phenyl- or p-tolylsulfonyloxy).

The compounds in which R² is OH or L′ can be obtained by reduction, forexample, from compounds in which Y and R² together form a carbonylgroup.

The reduction can take place as indicated by catalytic hydrogenation, orwith complex metal hydrides.

Examples of complex metal hydrides which can be employed are NaBH₄,diisobutylaluminium hydride or NaAl(OCH₂CH₂OCH₃)₂H₂ and also diborane,with the addition if desired of catalysts such as BF₃, AlCl₃ or LiBr.Solvents suitable for this purpose are, in particular, ethers, such asdiethyl ether, di-n-butyl ether, THF, dioxane, diglyme or1,2-dimethoxyethane, and hydrocarbons, such as benzene. For a reductionwith NaBH₄, those solvents which are primarily suitable are alcoholssuch as methanol or ethanol, and also water, and aqueous alcohols. Inaccordance with these methods, reduction is carried out preferably attemperatures between −80 and +150° C., in particular between 0 and about100° C.

The conversion of an OH group into an OL′ group is effected by known andcustomary methods.

A base of the formula I can be converted into the associated acidaddition salt using an acid by means, for example, of reactingequivalent amounts of the base and the acid in an inert solvent such asethanol, followed by evaporative concentration. Particularly suitableacids for this reaction are those which form physiologically acceptablesalts. For instance, it is possible to use inorganic acids, examplesbeing sulfuric acid, nitric acid, hydrohalic acids such as hydrochloricor hydrobromic acid, phosphoric acids such as ortho-phosphoric acid,sulfamic acid, and also organic acids, especially aliphatic, alicyclic,araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic,sulfonic or sulfuric acids, examples being formic acid, acetic acid,propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinicacid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaricacid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinicacid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemonosulfonic andnaphthalenedisulfonic acids, and laurylsulfuric acid. Salts withphysiologically unacceptable acids, such as picrates, can be used toisolate and/or purify the compounds of the formula I.

The invention additionally provides for the use of the compounds of theformula I and/or their physiologically acceptable salts formanufacturing pharmaceutical preparations, especially by a non-chemicalroute. In this case they can be brought into a suitable dosage formtogether with at least one solid, liquid and/or semiliquid excipient orauxiliary and, if appropriate, in combination with one or more furtheractive substances.

The invention additionally provides pharmaceutical preparationscomprising an effective amount of at least one of the compounds of theformula I and/or one of their physiologically acceptable salts.

These preparations can be used as medicaments in human or veterinarymedicine. Suitable excipients are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration,topical application, or administration in the form of an inhalationspray and which do not react with the novel compounds, examples beingwater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glyceryl triacetate, gelatin, carbohydrates such as lactose orstarch, magnesium stearate, talc and vaseline. Plain tablets, pills,coated tablets, capsules, powders, granules, syrups, juices or drops areused in particular for oral administration, suppositories for rectaladministration, solutions, preferably oily or aqueous solutions, andalso suspensions, emulsions or implants, for parenteral administration,and ointments, creams or fine powders for topical application. The novelcompounds can also be lyophilised and the resultant lyophilisates used,for example, to manufacture preparations for injection. The preparationsindicated can be sterilized and/or may include auxiliaries such aslubricants, preservatives, stabilizers and/or wetting agents,emulsifiers, salts for influencing the osmotic pressure, buffersubstances, colorants, flavourings and/or a plurality of further activeingredients, such as one or more vitamins.

For administration as an inhalation spray it is possible to use sprayswhich comprise the active substance either dissolved or suspended in apropellant or mixture of propellants (e.g. CO₂ or chloro-fluorocarbons).In this case, the active substances are judiciously used in micronizedform with the possible presence of one or more additionalphysiologically compatible solvents, such as ethanol. Inhalationsolutions can be administered using customary inhalers.

The compounds of the formula I and their physiologically acceptablesalts can be used as excitatory amino acid antagonists in the combatingof diseases, especially for combating neurodegenerative disordersincluding cerebrovascular diseases, epilepsy, schizophrenia, Alzheimer'sdisease, Parkinson's disease and Huntington's disease, cerebralischaemias, infarcts and psychoses.

In these treatments, the compounds of the invention can generally beadministered in analogy to other known compounds having a similarprofile of action, such as ifenprodil, preferably in doses of betweenabout 0.05 and 500 mg, in particular between 0.5 and 100 mg per doseunit. The daily dose is preferably between about 0.01 and 2 mg/kg ofbody weight. The specific dose for each patient, however, will depend ona wide variety of factors: for example, on the efficacy of the specificcompound employed, on the age, body weight, general state of health,sex, diet, time and route of administration, rate of excretion,medicament combination and severity of the respective disorder to whichthe therapy is applied. Parenteral administration is preferred.

Above and below, all temperatures are indicated in °C. In the examplesbelow, “customary workup” means: water is added if necessary, themixture is adjusted to a pH of between 2 and 10 if necessary, dependingon the constitution of the end product, the mixture is extracted withethyl acetate or dichloromethane, the organic phase is separated off,dried over sodium sulfate and concentrated by evaporation, and theresidue is purified by chromatography on silica gel and/or bycrystallization.

EXAMPLE 1

A suspension of 5.5 g of 6-(3-chloropropyl)-3H-benzoxazol-2-one in 50 mlof ethanol is admixed with 5.7 g of 4-(4-fluorobenzyl)piperidinehydrochloride and 7.2 ml of triethylamine. The mixture is stirred underreflux for one hour and subjected to customary workup to give 8.5 g of6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-3H-benzoxazol-2-one, m.p.105-107°.

EXAMPLE 2

A solution of 6.7 g of6-{3-[4-(4-fluorobenzyl)piperid-1-yl]-1-hydroxypropyl}-3H-benzoxazol-2-one[obtainable by hydrogenation of6-{3-[4-(4-fluorobenzyl)piperid-1-yl]-1-oxopropyl}-3H-benzoxazol-2-one,which can be obtained by reacting 4-(4-fluorobenzyl)piperidine and6-(3-chloropropionyl)-3H-benzoxazol-2-one] in 70 ml of dioxane is heatedunder reflux with 7 ml of concentrated HCl for 1.5 h. The mixture iscooled and 8.5 g of NaHCO₃ and 70 ml of water are added. 30 ml ofdichloromethane are added and the mixture is stirred for 30 minutes. Theprecipitate is separated off, washed with acetone and ether and dried togive 5.7 g of6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzoxazol-2-one(“A”), m.p. 202-203.5°; hydrochloride: m.p. 220-223°.

The following compounds are obtained analogously:

6-{3-[4-(4-fluorobenzyl)piperid-1-yl]-2-methylpropenyl}-3H-benzoxazol-2-one,m.p. 156-160°, hydrochloride: 230-235°;

6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzothiazol-2-one,hydrochloride×H₂O, m.p. 95-99° (decomposition);

5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-dihydrobenzimidazol-2-one,m.p. 218-220°; hydrochloride: 243-245°.

5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-dihydroindol-2-one;

6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3,4-dihydro-1H-quinolin-2-one.

EXAMPLE 3

A solution of 2.56 g of “A” in 100 ml of methanol and 100 ml of THF ishydrogenated at room temperature with addition of 1.2 g of Pd/C. Thecatalyst is separated off and the mixture is subjected to customary workup to give 1.31 g of6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-3H-benzoxazol-2-one, m.p.105-107°.

The following compounds are obtained analogously, by hydrogenation:

from6-{3-[4-(4-fluorobenzyl)piperid-1-yl]-2-methylpropenyl}-3H-benzoxazol-2-one

6-{3-[4-(4-fluorobenzyl)piperid-1-yl]2-methylpropyl}-3H-benzoxazol-2-one;

from6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzothiazol-2-one:

6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-3H-benzothiazol-2-one;

from5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-dihydrobenzimidazol-2-one:

5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-1,3-dihydrobenzimidazol-2-one;

from5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-dihydroindol-2-one:

5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-1,3-dihydroindol-2-one;

from6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3,4-dihydro-1H-quinolin-2-one:

6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-3,4-dihydro-1H-quinolin-2-one.

The following examples relate to pharmaceutical preparations:

EXAMPLE A

Injection Vials

A solution of 100 g of the active substance of the formula I and 5 g ofdisodium hydrogen phosphate in 3 l of double-distilled water is adjustedto a pH of 6.5 with 2 N hydrochloric acid, sterile-filtered, transferredto injection vials, lyophilized under sterile conditions andsterile-sealed. Each vial contains 5 mg of active substance.

EXAMPLE B

Suppositories

A mixture of 20 g of the active substance of the formula I is meltedtogether with 100 g of soya lecithin and 1400 g of cocoa butter and themixture is poured into moulds and left to cool. Each Suppositorycontains 20 mg of active substance.

EXAMPLE C

Solution

A solution is prepared from 1 g of the active substance of the formulaI, and 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O and 0.1 g ofbenzalkonium chloride in 940 ml of double-distilled water. The pH isadjusted to 6.8, and the solution is made up to 1 l and sterilized byirradiation. This solution can be used in the form of eyedrops.

EXAMPLE D

Ointment

500 mg of the active substance of the formula I are mixed with 99.5 g ofvaseline under aseptic conditions.

EXAMPLE E

Tablets

A mixture of 1 kg of active substance of the formula I, 4 kg of lactose,1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearateis compressed into tablets in a customary manner such that each tabletcontains 10 mg of active substance.

EXAMPLE F

Coated tablets

Tablets are pressed as in Example E and are then coated in a customarymanner with a coating of sucrose, potato starch, talc, tragacanth andcolorant.

EXAMPLE G

Capsules

2 kg of active substance of the formula I are filled into hard gelatinecapsules in a customary manner such that each capsule contains 20 mg ofactive substance.

EXAMPLE H

Ampoules

A solution of 1 kg of active substance of the formula I in 60 l ofdouble-distilled water is sterile-filtered, filled into ampoules andlyophilized under sterile conditions and the ampoules aresterile-sealed. Each ampoule contains 10 mg of active substance.

EXAMPLE I

Inhalation spray

14 g of active substance of the formula I are dissolved in 10 l ofisotonic NaCl solution and the solution is filled into customarycommercial spray containers having a pump mechanism. The solution can besprayed into the mouth or nose. One burst of spray (about 0.1 ml)corresponds to a dose of about 0.14 mg.

What is claimed is:
 1. A compound which is a)6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzoxazol-2-one; b)6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-3H-benzoxazol-2-one; c)6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzothiazol-2-one; d)5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-benzimidazol-2-one ore)5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-dihydroindol-2-one.2. A compound according to claim 1 which is a)6-{3-[4-(4-fluorobenzyl)piperid-1-yl}propenyl}-3H-benzoxazol-2-one b)6-{3-[4-(4-fluorobenzyl)piperid-1-yl}propyl}-3H-benzoxazol-2-one; or c)6-{3-[4-(4-fluorobenzyl)piperid-1-yl}propenyl}-3H-benzothiazol-2-one. 3.A process for preparing6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzoxazol-2-one,6-{3-[4-(4-fluorobenzyl)piperid-1yl]propyl}-3H-benzoxazol-2-one,6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzothiazol-2-one,5-{3-[4-(4-fluorobenzyl)piperid-1-yl]prophenyl}-1,3-benzimidazol-2-oneor5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-dihydroindol-2-one,or a salt thereof, comprising a) reacting a compound of the formula II

 in which L is Cl, Br, I, OH or a reactively esterified OH group, andR¹, R² and R³ are H X is O, N, CH, or S, Y is CH, Z is CH, or Y and Ztogether are alternatively C═C  with a compound of the formula III

in which R⁴ is F, and is in the 4 position. or b) hydrogenating acompound of formula I

 in which X is O, N, CH, or S, Y and Z together are C═C R¹, R² and R³are H, R⁴ is F, and is in the 4 position, or c) eliminating water or L′Hfrom a compound of formula

 in which R¹ is OH or L′, in which L′ is Cl, Br, I, or a reactivelyesterified OH group, R² and R³ are H, R⁴ is F, and is in the 4 position,X is O, N, CH, or S, Y is CH, and Z is CH, and/or d) converting6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzoxazol-2-one,6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propyl}-3H-benzoxazol-2-one,6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzothiazol-2-one,5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-benzimidazol-2-one,or5-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-1,3-dihydroindol-2-one,by treatment with an acid into one of its salts.
 4. A process forpreparing a pharmaceutical composition comprising bringing a compoundaccording to claim 1 and/or one of its physiologically acceptable saltsinto a suitable dosage form together with at least one solid, liquid orsemiliquid excipient or auxiliary.
 5. A pharmaceutical compositioncomprising an effective amount of at least one compound of claim 1and/or a physiologically acceptable salt thereof.
 6. A process fortreating or prophylaxis of strokes or cerebral oedemas comprisingadministering to a host in need thereof an effective amount of acompound according to claim 1, or a physiologically acceptable saltthereof.
 7. A process for treating or protecting against cerebraloedemas comprising administering to a host in need thereof an effectiveamount of a compound according to claim 1, or a physiologicallyacceptable salt thereof.
 8. A process for treating or protecting againsthypoxia comprising administering to a host in need thereof an effectiveamount of a compound according to claim 1, or a physiologicallyacceptable salt thereof.